Niemann-Pick Disease, type C1 (NPC1) is a neurodegenerative disorder due to a defect in intracellular lipid and cholesterol transport. As part of a Bench-to-Bedside initiative, we initiated a clinical protocol focused on identifying and characterizing biomarkers that could be used in a subsequent therapeutic trial. Funding to support a research nurse was provided by both the Ara Parseghian Medical Research Foundation and Danas Angels Research Trust. This protocol was initiated in August 2006, and to date we have enrolled over 120 NPC patients. This is the largest cohorts of actively followed patients in this country. While most of the patients are children, the patients range in age from infants to adults. This protocol involves neurological, hearing, ophthalmological, psychiatric and medical evaluations. Blood, urine, and cerebral spinal fluid are being collected for biomarker analysis. Evaluations include magnetic resonance imaging combined with spectroscopy and auditory brainstem responses. We plan to continue to enroll new patients and follow this group over time. This initial observational study was instrumental in laying the foundation for a therapeutic trial of N-acetyl cysteine that was initiated in September 2009. This trial was a placebo-controlled, cross-over trial that enrolled 35 NPC patients. This trial was completed in August 2010. In early 2013 we initiate a phase 1/2 trial of hydroxypropyl-beta-cyclodextran administered directly to the central nervous system in collaboration with the Therapuetics and Rare Disease Section of NCATS and multiple extramural investigators. We have recently completed a multicenter, multinational Phase 2b/3 trial that was initiated in 2016. We have now initiated in collaboration with Washington University a trial of hydroxypropyl-beta-cyclodextrin in infants with severe liver disease due to NPC1 and a trial of combined intravenous and intrathecal hydroxypropyl-beta-cyclodextrin in NPC1 patients with chronic, subacute liver disease. In the fall of 2014, we initiated a phase 1/2 trail of vorinostat which has now been completed. This will provide a proof of principle for use of an HDAC inhibitory for NPC1 therapy. This trial was supported by one of the new U01 grants through the NIH Clinical Center. Recent efforts have focused on newborn screening for NPC1 and exploring opportunities for future clinical trials.